1. Field of the Invention
The penicillin derivatives of the present invention possess in general the usual attributes of that family of antibacterial agents and are particularly useful in the treatment of bacterial infections by both oral and parenteral administration.
2. Description of the Prior Art
The semi-synthetic penicillins D(-)-.alpha.-aminobenzyl-penicillin (ampicillin) and D(-)-.alpha.-amino-p-hydroxybenzylpenicillin (amoxicillin) are disclosed in U.S. Pat. Nos. 2,985,648 (ampicillin) and 3,674,776 (amoxicillin). While these penicillins possess a broad spectrum of antibacterial activity and can be administered both orally and parenterally, problems have been encountered in obtaining dosage forms suitable for intravenous administration. Thus, the only form of ampicillin generally available for intravenous injection has been the water-soluble sodium salt. The agueous solution of this salt, however, has an extremely short shelf-life (about one hour at room temperature when reconstituted at 250 mg./ml.) and the solution is somewhat irritating on injection, presumably due to its high pH. In addition, the sodium salt of ampicillin is hygroscopic and cannot be prepared by lyophilization. With respect to amoxicillin, no parenteral dosage form of this antibiotic is presently being marketed. A crystalline sodium salt of amoxicillin has not yet been made and the crystalline potassium salt can be made only with great difficulty, e.g. preparation by lyophilization is not possible. The potassium salt, moreover, when reconstituted with water to a concentration of 250 mg./ml., is stable for only 15 minutes at room temperature and precipitates out of solution on standing.
Various aldehyde and ketone condensation products of .alpha.-aminopenicillins including ampicillin and amoxicillin have been disclosed in the patent and scientific literature. Thus, for example, derivatives of various .alpha.-aminopenicillins with nitro-substituted heterocyclic aldehydes are disclosed in U.S. Pat. No. 3,647,781. Condensation products of ampicillin or ring-substituted ampicillins with aromatic heterocyclic aldehydes are disclosed in U.K. Pat. No. 1,436,959. Other patent publications disclosing derivatives of .alpha.-aminopenicillins with aldehydes or ketones include U.S. Pat. Nos. 3,198,804 and 3,558,602 (various aldehydes and ketones), U.S. Pat. No 3,198,788 and South African Pat. No. 72/8475 (formaldehyde), U.S. Pat. No. 3,230,214 (aromatic or heteroaromatic aldehydes containing an ortho hydroxyl substituent), U.S. Pat. No. 3,325,479 (diketones), U.S. Pat. Nos. 3,489,746, 3,549,746, 3,814,800 and U.K. Pat. No. 1,224,619 (acetone), U.S. Pat. No. 3,725,389 (N-substituted-4-piperidones), U.S. Pat. NO. 3,888,848 (chloral hydrate), U.S. Pat. No. No. (various aldehydes) and South African Pat. No. 72/8474 (acetaldehyde). While certain of these derivatives, e.g. hetacillin, the acetone adduct of amplicillin, are disclosed as being somewhat more stable in aqueous solution as sodium salts than the parent penicillins, it would be a substantial advantage to the physician if reconstituted solutions of ampicillin and amoxicillin (or derivatives of these penicillins which completely and rapidly hydrolyze in aqueous solution to form ampicillin and amoxicillin) were stable for longer periods of time.
It is, accordingly, an object of the present invention to provide new water-soluble forms of ampicillin and amoxicillin which can be administered both orally and parenterally (including intravenous administration) and which do not have the disadvantages associated with the known intravenous forms of these penicillins, i.e. the alkali metal salts. In particular, it is an object of the present invention to provide new derivatives of ampicillin and amoxicillin which (1) upon the addition of water will give true solutions of ampicillin or amoxicillin suitable for both oral and parenteral administration, (2) have acceptable thermal stability in the solid state, (3) in aqueous solution at a concentration of about 250 mg./ml. have a useful life of at least several hours at room temperature, (4) result in reduced irritation on parenteral administration and (5) can be readily and simply prepared by lyophilization as well as by solvent precipitation methods. These and other objects of the present invention will be apparent from the followijng description.